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Biomedical subjects

Hiroyuki Nakamura

Publications and source records attributed to Hiroyuki Nakamura.

At least 19 recordsLinked to original sources
PubMed2026

Polygenic risk scores and lifestyle factors predicting new onset of type 2 diabetes in the Japanese general population.

PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk prediction beyond traditional risk factors. METHODS: We conducted a cross-sectional and a longitudinal study using the Shika resident cohort (n = 895) and the Toshiba worker cohort (n = 7019), respectively. Participants were categorized into low, intermediate, and high genetic risk groups using PRS constructed with genome-wide association study data from East Asian populations. We defined diabetes based on hemoglobin A1c, fasting blood glucose, self-reported diagnosis, or medication use. The associations of PRS and lifestyle factors with diabetes development were analyzed using multivariate logistic regression and Cox proportional hazards models. RESULTS: Higher PRS were associated with increased diabetes risk in both cohorts (resident cohort: odds ratio 4.51, 95% CI 2.53-8.04; worker cohort: hazard ratio 1.50, 95% CI 1.23-1.83 for high vs low PRS), which remained consistent across age, body mass index, and comorbidities. Regular exercise, absence of hypertension, and absence of dyslipidemia were associated with lower diabetes risk, particularly in the high PRS group. The addition of PRS to conventional prediction models improved the discrimination of diabetes risk. MAIN CONCLUSION: PRS are associated with diabetes risk in Japanese general populations, independent of traditional risk factors. Nonetheless, healthy lifestyle habits may reduce diabetes risk even among genetically susceptible individuals, which support the utility of PRS for personalized diabetes risk assessment and prevention strategies.

Adult↗
PubMed2025

The SELENOP Polymorphism rs7579 Predicts Hepatic Steatosis in Females With Insulin Resistance in the General Population.

CONTEXT: Selenoprotein P is a hepatokine associated with several metabolic processes. Rs7579 (C > T) is a SeP-related functional single nucleotide polymorphism. OBJECTIVE: In this study, we aimed to identify the environmental factors affecting the relationship between rs7579 and metabolic diseases, such as metabolic dysfunction-associated steatotic liver disease, in the general population. METHODS: This cross-sectional study was based on the Shika Study, a survey of residents in the Noto Peninsula of Ishikawa Prefecture. We analyzed a total of 900 adults, measuring full-length selenoprotein P (FL-SeP) serum levels using a sol-particle homogeneous immunoassay. RESULTS: We observed that selenium and FL-SeP serum levels were associated with dyslipidemia. In males, serum selenium was associated with dyslipidemia and hepatic steatosis. However, in females, FL-SeP tended to be associated with diabetes. Participants carrying the TT genotype and hepatic steatosis exhibited higher levels of liver enzymes, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), and the homeostasis model assessment of β-cell function than those without hepatic steatosis or with other genotypes. In females carrying the TT genotype of rs7579, hepatic steatosis, hypertension, diabetes, obesity, and metabolic syndrome were associated with higher HOMA-IR levels. CONCLUSION: In this study, we revealed that the association between metabolic diseases and HOMA-IR differed single nucleotide polymorphism genotype and sex dependently. In females carrying the TT genotype of rs7579, hepatic steatosis-associated metabolic disorders (diabetes, hypertension, obesity, and metabolic syndrome) were associated with higher HOMA-IR. The results of this study open the way to genetic signatures-based personalized preventive medicines.

CCDC152↗
PubMed2007

Synthesis of boron cluster lipids: closo-dodecaborate as an alternative hydrophilic function of boronated liposomes for neutron capture therapy.

We succeeded in the synthesis of the double-tailed boron cluster lipids 4a-c and 5a-c, which have a B12H11S moiety as a hydrophilic function, by S-alkylation of B12H11SH (BSH) with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols for a liposomal boron delivery system on neutron capture therapy. Calcein encapsulation experiments revealed that the liposomes, prepared from the boron cluster lipid 4b, DMPC, PEG-DSPE, and cholesterol, are stable at 37 degrees C in FBS solution for 24 h. [reaction: see text].

Animals↗
PubMed2006

Occlusal disharmony induces spatial memory impairment and hippocampal neuron degeneration via stress in SAMP8 mice.

We examined the effect of occlusal disharmony in senescence-accelerated (SAMP8) mice on plasma corticosterone levels, hippocampal neuron number, and spatial performance in the water maze. The bite-raised condition was associated with an accelerated age-related decline in spatial memory, increased plasma corticosterone levels, and a decreased number of neurons in the hippocampal CA3 region. The findings suggest that the bite-raised condition in aged SAMP8 mice induces hippocampal neuron loss, thereby leading to senile memory deficits.

Aging↗
PubMed2006

Brain-derived neurotrophic factor participates in determination of neuronal laminar fate in the developing mouse cerebral cortex.

Lamina formation in the developing cerebral cortex requires precisely regulated generation and migration of the cortical progenitor cells. To test the possible involvement of brain-derived neurotrophic factor (BDNF) in the formation of the cortical lamina, we investigated the effects of BDNF protein and anti-BDNF antibody separately administered into the telencephalic ventricular space of 13.5-d-old mouse embryos. BDNF altered the position, gene-expression properties, and projections of neurons otherwise destined for layer IV to those of neurons for the deeper layers, V and VI, of the cerebral cortex, whereas anti-BDNF antibody changed some of those of neurons of upper layers II/III. Additional analysis revealed that BDNF altered the laminar fate of neurons only if their parent progenitor cells were exposed to it at approximately S-phase and that it hastened the timing of the withdrawal of their daughter neurons from the ventricular proliferating pool by accelerating the completion of S-phase, downregulation of the Pax6 (paired box gene 6) expression, an essential transcription factor for generation of the upper layer neurons, and interkinetic nuclear migration of cortical progenitors in the ventricular zone. These observations suggest that BDNF participates in the processes forming the neuronal laminas in the developing cerebral cortex. BDNF can therefore be counted as one of the key extrinsic factors that regulate the laminar fate of cortical neurons.

Animals↗
PubMed2006

Vanadate-induced activation of cytosolic phospholipase A2alpha in L929 cells: Roles of tyrosine kinase, protein kinase C, and extracellular signal-regulated kinase.

Orthovanadate (Na3VO4), which acts as an inhibitor of protein tyrosine phosphatases, has a various pharmacological effects including the release of arachidonic acid (AA) from cells. We investigated roles of alpha-type cytosolic phospholipase A2 (cPLA2alpha), Src family kinases (Src) and protein kinase C (PKC) in the release of AA induced by Na3VO4 from a murine fibroblast cell line, L929. C12 cells, a variant of L929 that lacks expression of cPLA2alpha, were used along with a clone of C12 cells that are stably expressing cPLA2alpha (C12-cPLA2alpha cells). In the presence of a Ca2+ ionophore (10 microM A23187), 5 and 10mM Na3VO4 synergistically stimulated AA release from L929 and C12-cPLA2alpha cells, and to a much lesser extent from control C12 cells. The release of AA by Na3VO4/A23187 was inhibited by a selective cPLA2alpha inhibitor (3 microM pyrrophenone). The release of AA by Na3VO4/A23187 was significantly inhibited by a PKC inhibitor (10 microM GF109203X), in PKC-depleted cells, by a Src inhibitor (2 microM PP2) and by an inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2) kinase (10 microM U0126). The phosphorylation of ERK1/2 was stimulated by Na3VO4, and the response was significantly decreased by inhibitors of Src, PKC and ERK1/2 kinase. Our data show that Na3VO4 stimulates AA release largely via cPLA2alpha activation in Ca2+-dependent manner, and the cross-talk between Src and PKC and the ERK-dependent pathways are involved in Na3VO4-induced AA release from L929 cells.

Animals↗
PubMed2006

Genotypes and haplotypes of CCR2 and CCR3 genes in Japanese cedar pollinosis.

Whole genome scan analyses have revealed that the chromosomal region 3p21.3, which contains a gene cluster of the CC chemokine receptor, is possibly critical for the pathogenesis of allergic inflammation. Japanese cedar pollinosis is mediated by a type I allergy and induces seasonal rhinitis and conjunctivitis in humans as the most common form of hay fever in spring in Japan, although the candidate genes for cedar pollinosis remain to be elucidated. We sequenced CCR1, CCR2, CCR3, CCR5, and CCXCR1 using the PCR restriction fragment length polymorphism method in subjects with cedar pollinosis and controls. We found 8 polymorphisms of A111G, Arg127Cys and Arg252Gln in CCXCR1, T885C in CCR1, Val64Ile and T780C in CCR2, T51C in CCR3 and Arg223Gln in CCR5. The transmission disequilibrium test using 60 children with pollinosis and their parents and an association study using unrelated adult subjects (151 patients and 157 controls) showed a significant association of 64Ile in CCR2 and 51C in CCR3 with cedar pollinosis. The frequency of haplotype 64Ile/780C/51C in pollinosis was significantly higher than in controls. Our results suggest that CCR2 and CCR3 genes are candidate genes for Japanese cedar pollinosis.

Adult↗
PubMed2006

Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases.

A series of benzamidines and benzamides was synthesized as selective inhibitors of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, and tested for inhibitory activity toward autophosphorylation by the enzyme assay. Selective inhibition of VEGFR-2 tyrosine kinase was observed in the salicylic amide 4e and the anthranilic amidine 5a, and their percent inhibitions of VEGFR-2 tyrosine kinase were 44-60% at a 10 microM concentration of compounds. The salicylic amide 4a showed inhibition of both VEGFR-1 and VEGFR-2 tyrosine kinases at a 10 microM concentration.

Animals↗
PubMed2006

Cortical feedback depolarization waves: a mechanism of top-down influence on early visual areas.

Despite the lack of direct evidence, it is generally believed that top-down signals are mediated by the abundant feedback connections from higher- to lower-order sensory areas. Here we provide direct evidence for a top-down mechanism. We stained the visual cortex of the ferret with a voltage-sensitive dye and presented a short-duration contrast square. This elicited an initial feedforward and lateral spreading depolarization at the square representation in areas 17 and 18. After a delay, a broad feedback wave (FBW) of neuron peak depolarization traveled from areas 21 and 19 toward areas 18 and 17. In areas 18 and 17, the FBW contributed the peak depolarization of dendrites of the neurons representing the square, after which the neurons decreased their depolarization and firing. Thereafter, the peak depolarization surrounded the figure representation over most of areas 17 and 18 representing the background. Thus, the FBW is an example of a well behaved long-range communication from higher-order visual areas to areas 18 and 17, collectively addressing very large populations of neurons representing the visual scene. Through local interaction with feedforward and lateral spreading depolarization, the FBW differentially activates neurons representing the object and neurons representing the background.

Animals↗
PubMed2006

Hydrogen peroxide-induced arachidonic acid release in L929 cells; roles of Src, protein kinase C and cytosolic phospholipase A2alpha.

Hydrogen peroxide (H(2)O(2)) stimulates the release of arachidonic acid from cells, but the signaling mechanism(s) involved remains to be elucidated. We investigated the roles of alpha-type cytosolic phospholipase A(2) (cPLA(2)alpha), Src family kinases (Src) and protein kinase C (PKC) in the release of arachidonic acid from L929 cells (a murine fibroblast cell line), C12 cells (a variant of L929 that lacks cPLA(2)alpha) and a stable clone of C12 cells expressing cPLA(2)alpha (C12-cPLA(2)alpha cells). In the presence of 10 muM A23187, 100 nM phorbol myristate acetate (PMA) and 1 mM H(2)O(2) synergistically stimulated arachidonic acid release from L929 cells and C12-cPLA(2)alpha cells, and to a much lesser extent from C12 cells. The reagents alone and co-treatment with PMA and H(2)O(2) without A23187 had marginal effects. No arachidonic acid was released by PMA/A23187 or H(2)O(2)/A23187 in CaCl(2)-free buffer and the release was inhibited by a selective cPLA(2)alpha inhibitor (3 microM pyrrophenone). Addition of 10 microM H(2)O(2), which did not stimulate arachidonic acid release with A23187, enhanced the response to PMA/A23187. The release induced by PMA/A23187 and by H(2)O(2)/A23187 was significantly inhibited by a PKC inhibitor (10 microM GF109203X) and in PKC-depleted cells, and by a Src inhibitor (2 microM PP2). The phosphorylation of extracellular signal-regulated kinase 1/2 induced by PMA/A23187 and H(2)O(2)/A23187 was significantly decreased by inhibitors of PKC and Src. These findings suggest that H(2)O(2) with Ca(2+) stimulates arachidonic acid release via cPLA(2)alpha in a Src- and PKC-dependent manner in L929 cells. The role of cross-talk between Src and PKC in arachidonic acid release is discussed.

Animals↗
PubMed2006

Projections of glutamate decarboxylase positive and negative cerebellar neurons to the pretectum in the cat.

The pretectum is one of the primary visual centers, and plays an important role in the visuomotor reflexes. It also receives projections from the cerebellar nuclei that are considered to regulate these reflexes. Gamma aminobutylic acid (GABA) and glutamate are supposed to be two major neurotransmitters of the projection neurons of the cerebellar nuclei. We double labeled the projecting neurons with a tracer, biotinylated dextran amine (BDA), and with an antiserum to glutamate decarboxylase (GAD), the enzyme that synthesizes GABA. The results indicated that about 40% of the pretectal-projecting neurons of the cerebellar nuclei were GAD immunoreactive. The GAD positive pretectal-projecting neurons were significantly smaller than the GAD negative projecting neurons. Our findings thus suggest the existence of two distinct cerebello-pretectal projection systems: one is mediated by GABAergic inhibitory projections, while the other is mediated by non-GABAergic, probably glutamatergic excitatory ones.

Animals↗
PubMed2006

Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis.

A number of small GTPases are involved in cancer cell proliferation, migration and invasion, acting as molecular switches that cycle between GTP- and GDP-bound states. GTPase-activating proteins (GAPs) have been established as a major class of negative regulators of Rho GTPase signaling. To investigate the biological function of p190 RhoGAP toward RhoA in cancer cell invasion and metastasis, we generated a chimera made of the RhoGAP domain of p190 and the C-terminus of RhoA (p190-RhoA chimera), and transfected it into human pancreatic cancer cells, AsPC-1. Epidermal growth factor (EGF)-induced activation of RhoA, as well as RhoB and RhoC, to a lesser extent, was significantly inhibited in p190-RhoA chimera-transfected AsPC-1 cells compared with that of control cells (mock-infected), when assessed by pull-down assay for GTP-bound RhoA, RhoB, and RhoC, respectively. EGF-induced invasion of p190-RhoA chimera transfectants was significantly inhibited compared with that of mock-infected cells in a modified Boyden chamber assay. Furthermore, the mice injected intrasplenically with AsPC-1 cells that overexpressed the p190-RhoA chimera had a marked reduction in the number and size of metastatic nodules in the liver. These data suggest that the inhibitory action of p190 RhoGAP toward RhoA offers a novel approach to the treatment of invasion and metastasis of cancer cells.

Animals↗
PubMed2006

Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders.

OBJECTIVE: To investigate whether matrix metalloproteinases (MMPs) and/or aggrecanase in synovial fluid can be used as biochemical markers in the diagnosis of internal derangement (ID) of the temporomandibular joint (TMJ). STUDY DESIGN: Forty-four samples of synovial fluid were obtained from 35 patients with ID and osteoarthritis (OA) and 15 normal samples from 10 asymptomatic volunteers. MMP-2, -9, and aggrecanase in the synovial fluid were examined by immunoblotting. RESULTS: The incidences of MMP-2, -9, and aggrecanase expression in the ID and OA group were significantly higher than those in the normal group (P < .05). Those with anterior disc displacement without reduction and severe OA showed significantly high expression of MMP-9 compared with other disease subgroups (P < .05). Conversely, comparatively high expression of MMP-2 and aggrecanase was shown in the early-stage OA group. However, there was no significant difference in expression of MMP-2 and aggrecanase among disease subgroups. CONCLUSIONS: These findings suggested that expression of aggrecanase could be a potential biochemical marker for articular cartilage degradation in ID of the TMJ.

Adolescent↗
PubMed2006

1,2-Bis(diphenylphosphino)carborane as a dual mode ligand for both the Sonogashira coupling and hydride-transfer steps in palladium-catalyzed one-pot synthesis of allenes from aryl iodides.

[reaction: see text] One-pot allene synthesis from aryl iodides 1 and propargyldicyclohexylamine 2 proceeded in the presence of Pd(2)(dba)(3).CHCl(3) catalyst (2.5 mol %), 1,2-bis(diphenylphosphino)carborane 5 (10 mol %), CuI (15 mol %), and Et(3)N (150 mol %) to give the corresponding allenes 4 in good to high yields. Electron-deficient bidentate phosphines, such as 1,2-bis(diphenylphosphino)carborane 5 and (C(6)F(5))(2)PC(2)H(4)P(C(6)F(5))(2), play the role of a dual mode ligand for both the Sonogashira coupling and hydride-transfer reactions.

Journal Article↗
PubMed2006

Up-regulation of cytosolic phospholipase A2alpha expression by N,N-diethyldithiocarbamate in PC12 cells; involvement of reactive oxygen species and nitric oxide.

Disulfiram (an alcohol-aversive drug) and related compounds are known to provoke several side effects involving behavioral and neurological complications. N,N-diethyldithiocarbamate (DDC) is considered as one of the main toxic species of disulfiram and acts as an inhibitor of superoxide dismutase. Since arachidonic acid (AA) formation is regulated by reactive oxygen species (ROS) and related to toxicity in neuronal cells, we investigated the effects of DDC on AA release and expression of the alpha type of cytosolic phospholipase A(2) (cPLA(2)alpha) in PC12 cells. Treatment with 80-120 microM DDC that causes a moderate increase in ROS levels without cell toxicity stimulated cPLA(2)alpha mRNA and its protein expression. The expression was mediated by extracellular-signal-regulated kinase (ERK1/2), one of the mitogen-activated protein kinases. Treatment with N(G) nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase, 1 mM) and oxy-hemoglobin (a scavenger of nitric oxide, 2 mg/mL) abolished the DDC-induced responses (ERK1/2 phosphorylation and cPLA(2)alpha expression). We also showed DDC-induced up-regulation of the mRNA expression of lipocortin 1, an inhibitor of PLA(2). Furthermore, DDC treatment of the cells enhanced Ca(2+)-ionophore-induced AA release in 30 min, although the effect was limited. Changes in AA metabolism in DDC-treated cells may have a potential role in mediating neurotoxic actions of disulfiram. In this study, we show the first to demonstrate the up-regulation of cPLA(2)alpha expression by DDC treatment in neuronal cells.

Animals↗
PubMed2006

Percutaneous CT-guided radiofrequency ablation of pulmonary malignant tumors: preliminary report.

OBJECTIVE: Radiofrequency ablation (RFA) is frequently used for hepatic malignant tumors, but few reports discuss its use for lung tumors. We report our pilot clinical study with RFA for the treatment of pulmonary malignant tumors. PATIENTS AND METHODS: Five patients with histologically-proven malignant primary and three metastatic lung tumors underwent a total of 11 RFA procedures. RFA was performed in two patients as palliative therapy to shrink the tumors and in six as radical therapy. All RFA was performed by the percutaneous CT-guided approach. RESULTS: Three tumors were completely ablated by one procedure. Contrast CT revealed cyst cavity formation or scar formation at these three tumors. Gd contrast-enhanced MRI revealed cystic lesions with ringlike enhancement or scar formation. Partial ablation after the first procedure was noted in six tumors including the two palliative cases. RF ablation was well tolerated in all patients. Intraprocedural complications included six cases of pneumothorax (one patient required chest tube placement), six cases of pleural effusion (two patients required chest tube placement), one case of pneumonia (improved immediately with antibiotics), three cases of bloody sputum (mild), and six cases of chest pain (all cases after the procedure). CONCLUSIONS: This pilot clinical study demonstrates that CT-guided RFA is a relatively safe and effective treatment option for malignant lung tumors. Additional trials are needed to determine the safety, efficacy, and optimal indications of RFA.

Aged↗
PubMed2006

Ceramide-1-phosphate activates cytosolic phospholipase A2alpha directly and by PKC pathway.

Ceramide-1-phosphate (C1P), a novel bioactive sphingolipid, is implicated in the vital cellular processes such as cell proliferation and inflammation. The role of C1P on activity of cytosolic phospholipase A2alpha (cPLA2alpha), a key enzyme for the release of arachidonic acid (AA) and prostanoids, has not been well elucidated. In this study, we investigated the effect of C1P on the release of AA from L929 cells and a variant, which lacks cPLA2alpha expression, C12 cells. C1P at 30 microM alone induced AA release from L929 cells without an increase in intracellular Ca2+ concentration. C1P-induced AA release was marginal in C12 cells, and treatment with an intracellular Ca2+ chelator (BAPTA-AM) or an inhibitor of cPLA2alpha (2 microM pyrrophenone) decreased C1P-induced AA release in L929 cells. C1P increased the enzymatic activity of cPLA2alpha over two-fold in the presence of Ca2+. C1P triggered the translocation of cPLA2alpha and its C2 domain from the cytosol to the perinuclear region in CHO-K1 cells. Interestingly, C1P at 10 microM synergistically enhanced ionomycin-induced AA release from L929 cells. The AA release induced by C1P with and without ionomycin decreased by treatment with protein kinase C (PKC) inhibitor (10 microM GF109203X) and in the PKC-depleted cells. C1P at 10 microM stimulated the translocation of PKC (alpha and delta) from the soluble to the membrane fractions. We propose that C1P stimulates AA release via two mechanisms; direct activation of cPLA2alpha, and the PKC-dependent pathway.

Animals↗